Saxagliptin added to a submaximal dose of sulphonylurea improves glycaemic control compared with uptitration of sulphonylurea in patients with type 2 diabetes: a randomised controlled trial

Aims:Assess the efficacy and safety of saxagliptin added to a submaximal sulphonylurea dose vs. uptitration of sulphonylurea monotherapy in patients with type 2 diabetes and inadequate glycaemic control with sulphonylurea monotherapy.Methods and patients:A total of 768 patients (18-77 years; HbA(1c) screening >= 7.5 to < 10.0%) were randomised and treated with saxagliptin 2.5 or 5 mg in combination with glyburide 7.5 mg vs. glyburide 10 mg for 24 weeks. Blinded uptitration glyburide was allowed in the glyburide-only arm to a maximum total daily dose of 15 mg. Efficacy analyses were performed using ANCOVA and last-observation-carried-forward methodology.Results:At week 24, 92% of glyburide-only patients were uptitrated to a total glyburide dose of 15 mg/day. Saxagliptin 2.5 and 5 mg provided statistically significant adjusted mean decreases from baseline to week 24 vs. uptitrated glyburide, respectively, in HbA(1c) (-0.54%, -0.64% vs. +0.08%; both p < 0.0001) and fasting plasma glucose (-7, -10 vs. +1 mg/dl; p = 0.0218 and p = 0.002). the proportion of patients achieving an HbA(1c) < 7% was greater for saxagliptin 2.5 and 5 mg vs. uptitrated glyburide (22.4% and 22.8% vs. 9.1%; both p < 0.0001). Postprandial glucose area under the curve was reduced for saxagliptin 2.5 and 5 mg vs. uptitrated glyburide (-4296 and -5000 vs. +1196 mg center dot min/dl; both p < 0.0001). Adverse event occurrence was similar across all groups. Reported hypoglycaemic events were not statistically significantly different for saxagliptin 2.5 (13.3%) and 5 mg (14.6%) vs. uptitrated glyburide (10.1%).Conclusion:Saxagliptin added to submaximal glyburide therapy led to statistically significant improvements vs. uptitration of glyburide alone across key glycaemic parameters and was generally well tolerated.Jennifer Ciafullo, MPHUniversidade Federal de São Paulo, Ctr Diabet, São Paulo, BrazilCebu Doctors Univ Hosp, Cebu Doctors Univ Coll Med, Cebu, PhilippinesBristol Myers Squibb Co, Princeton, NJ USAUniversidade Federal de São Paulo, Ctr Diabet, São Paulo, BrazilWeb of Scienc

Insulin resistance in type 1 diabetes: what is ‘double diabetes’ and what are the risks?

In this review, we explore the concept of ‘double diabetes’, a combination of type 1 diabetes with features of insulin resistance and type 2 diabetes. After considering whether double diabetes is a useful concept, we discuss potential mechanisms of increased insulin resistance in type 1 diabetes before examining the extent to which double diabetes might increase the risk of cardiovascular disease (CVD). We then go on to consider the proposal that weight gain from intensive insulin regimens may be associated with increased CV risk factors in some patients with type 1 diabetes, and explore the complex relationships between weight gain, insulin resistance, glycaemic control and CV outcome. Important comparisons and contrasts between type 1 diabetes and type 2 diabetes are highlighted in terms of hepatic fat, fat partitioning and lipid profile, and how these may differ between type 1 diabetic patients with and without double diabetes. In so doing, we hope this work will stimulate much-needed research in this area and an improvement in clinical practice

O-GlcNAc Modification: Friend or Foe in Diabetic Cardiovascular Disease

O-Linked β-N-acetyl glucosaminylation (O-GlcNAcylation) is a dynamic post-translational modification that occurs on serine and threonine residues of cytosolic and nuclear proteins in all cell types, including those involved in the cardiovascular system. O-GlcNAcylation is thought to act in a manner analogous to protein phosphorylation. O-GlcNAcylation rapidly cycles on/off proteins in a time scale similar to that for phosphorylation/dephosphorylation of proteins. Several studies indicate that O-GlcNAc might induce nuclear localization of some transcription factors and may affect their DNA binding activities. However, at the cellular level, it has been shown that O-GlcNAc levels increase in response to stress and augmentation of this response suppresses cell survival. Increased levels of O-GlcNAc have been implicated as a pathogenic contributor to glucose toxicity and insulin resistance, which are major hallmarks of type 2 diabetes and diabetes-related cardiovascular complications. Thus, O-GlcNAc and its metabolic functions are not yet well-understood; focusing on the role of O-GlcNAc in the cardiovascular system is a viable target for biomedical investigation. In this review, we summarize our current understanding of the role of O-GlcNAc on the regulation of cell function and survival in the cardiovascular system

Reactive oxygen-derived free radicals are key to the endothelial dysfunction of diabetes.

Vascular complications are an important pathological issue in diabetes that lead to the further functional deterioration of several organs. The balance between endothelium-dependent relaxing factors and endothelium-dependent contracting factors (EDCFs) is crucial in controlling local vascular tone and function under normal conditions. Diabetic endothelial dysfunction is characterized by reduced endothelium-dependent relaxations and/or enhanced endothelium-dependent contractions. Elevated levels of oxygen-derived free radicals are the initial source of endothelial dysfunction in diabetes. Oxygen-derived free radicals not only reduce nitric oxide bioavailability, but also facilitate the production and/or action of EDCFs. Thus, the endothelial balance tips towards vasoconstrictor responses over the course of diabetes. © 2009 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd.postprin